Apurinic/apyrimidic endonuclease (Ape1), also known as redox effector factor (Ref-1) (hereinafter Ape1/Ref-1 or Ape1) is an enzyme with a dual role. In addition to its DNA base excision repair (BER) activity, Ape1/Ref-1 also functions as a redox effector maintaining transcription factors in an active reduced state.
Ape1/Ref-1 has been shown to stimulate the DNA binding activity of several transcription factors such as HIF-1α, NFκβ, AP-1 and p53, and others known and unknown, which are reportedly related to tumor survival and progression (Evans et al., Mutat Res 2000, 461, 83). Ape1/Ref-1 expression has been shown to be altered in a variety of cancers including breast, cervical, germ cell tumors, adult and pediatric gliomas, osteosarcomas, rhabdomyosarcomas, non-small cell lung cancer, and multiple myeloma (Puglisi et al., Oncol Rep 2002, 9, 11; Thomson et al., Am J Pediatr Hematol Oncol 2001, 23, 234; Roberston et al., Cancer Res 2001, 61, 2220; Puglisi et al., Anticancer Res 2001, 21, 4041; Koukourakis et al., Int J Radiat Oncol Biol Phys 2001, 50, 27; Kakolyris et al., Br J Cancer 1998, 77, 1169; Bobola et al., Clin Cancer Res 2001, 7, 3510). High Ape1/Ref-1 expression has also been associated with a poor outcome for chemoradiotherapy, poor complete response rate, shorter local relapse-free interval, poorer survival, and high angiogenesis (Koukourakis et al., Int J Radiat Oncol Biol Phys 2001, 50, 27; Kakolyris et al., Br J Cancer 1998, 77, 1169; Bobola et al., Clin Cancer Res 2001, 7, 3510).
Angiogenesis is an important component of cancer growth and metastasis. The formation of new blood vessels at the site of a cancerous tumor provides a source of nutrients for accelerated tumor growth and expansion as well as a path for tumor cells to enter the bloodstream and spread to other parts of the body. Thus, effective inhibition of angiogenesis is a useful mechanism to slow or prevent the growth and spread of cancer. An increase in Ape1/Ref-1 activity has been associated with angiogenesis. Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis and angiogenesis. Ape1/Ref-1 is a component of the hypoxia-inducible transcriptional complex formed on the vascular endothelial growth factor (VEGF) gene's hypoxic response element (Ziel et al., Faseb J 2004, 18, 986).
In addition to cancer, altered angiogenesis contributes to pathological conditions related to, among others, cardiovascular disease, chronic inflammatory disease, rheumatoid arthritis, diabetic retinopathy, degenerative maculopathy, retrolental fibroplasias, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, psoriasis, keloids, and systemic sclerosis Inhibition of angiogenesis is a desirable clinical outcome for the amelioration or prevention of diseases involving altered angiogenesis.
Given the role the redox site appears to have in pathologies, compounds and compositions for treating the diseases mediated by that site are needed.
It has been discovered that quinone compounds that include a secondary amide or acylhydroxylamine side chain are potent inhibitors of the redox function of Ape1, and therefore useful in treating cancers, and other diseases mediated by Ape1.
In one illustrative embodiment of the invention, compounds of the following formula are described herein:
or a pharmaceutically acceptable salt, hydrate, solvate, or morphological form thereof, wherein:
RA represents two substituents each independently selected from hydrogen and alkoxy, where RA are not both hydrogen; or
RA represents a fused aryl ring that is optionally substituted;
R is hydrogen or halo, or alkyl, heteroalkyl cycloalkyl, cycloheteroalkyl, alkoxy, heteroalkoxy cycloalkoxy, cycloheteroalkoxy, alkylthio, heteroalkylthio cycloalkylthio, or cycloheteroalkylthio, each of which is optionally substituted;
X is alkylene, alkenylene, or alkynylene, each of which is optionally substituted; and
Y is N(R1)2 or NR2OR2, where each R1 is independently selected from the group consisting of alkyl heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, or both R1 are taken together with the attached nitrogen to form an optionally substituted heterocycle; where each R2 is independently selected from the group consisting of hydrogen, alkyl heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, and a prodrug group, or both R2 are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle.
In addition, various genera and subgenera of the foregoing compounds are described herein. Such genera and subgenera are illustratively defined by various alternative embodiments of the groups RA, R, X, Y, R1, and R2. It is to be understood that all possible combinations of the various genera and subgenera of each of RA, R, X, Y, R1, and R2 are therefore described herein, and represent such additional illustrative embodiments of compounds of the invention. It is to be further understood that each of those additional illustrative embodiments of compounds may be used in any of the compositions, methods, and/or uses described herein.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with cancer, or other disease mediated by Ape1. It is to be understood that the compositions may include other component and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients with cancer, or other disease mediated by Ape1 are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient with cancer, or other disease mediated by Ape1. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with cancer, or other disease mediated by Ape1. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with cancer, or other disease mediated by Ape1 are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with cancer, or other disease mediated by Ape1.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating diseases mediated by Ape1, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of diseases mediated by Ape1.